Autism spectrum disorders (ASD) are a series of development disorders which include autistic disorder, Rett’s disorder, childhood disintegrative disorder, and Asperger’s syndrome. Autism spectrum disorders are classically characterized by, among others, severe and pervasive impairment in several areas of social and behavioural development (5). Recently, numerous basic science studies in mice and epidemiological studies in humans have revealed a link between Maternal Immune Activation (MIA) and ASD phenotypes (2-4, 6). Furthermore, instances of MIA leading to ASD like phenotypes appear to be primarily linked to immune activation in the first 2 trimesters (7). Herein, we will review several recent studies that begin to elucidate the mechanism linking MIA and ASD as well as the key role played by the maternal micorbiota in driving these pathways.
Hsiao et al. 2013, demonstrates GI barrier defects and microbiota alterations in the MIA model displaying offpsing with ASD-like phenotypes. Parrallelling epidemiological studies in humans that showed increased instances of IBD and other GI disorders were highly prevelant in ASD individuals (9). Investigators demonstrated that adult MIA offspring exhibited a number of similar GI defects, notably increased gut permeability as demonstrated by the translocation of dextran across the intestinal epithelium (8). The disbiosis of gut microbiota was also described in ASD individuals, and while a well defined ASD-assocaiated microbiota has not been established, rigorous examination of the composition of the ASD-associated microbiota revealed that while overall abundance of identified bacteria did not change, the alterations in the specific operational taxonomic units of both Clostridia and Bacteroidial were significant. Introduction of B. fragilis, which had been previously shown to emeleriate colitis (15) was able to correct the intestinal permeability in MIA offspring. In addition, administration of B. fragilis restored MIA-associated increases in IL-6, which has been previoulsy shown to be increased in MIA mothers and offspring (6, 10). Treatment with B. fragilis not only decreased the GI defects in MIA offspring, it also acted to return the microbiota toxonomy toward a more “normal” composition, reducing the disproportionate ratios found in MIA offspring. In addition to restoring the normal microbiota composition B. fragilis treatment also reduced ASD-like behavioural abnormalities. Suggesting a link between the microbiome and CNS that is still largely unexplored.
Next we examine the effect of the maternal microbiota on early postnatal immune system development as described by de Aguero et al.. Here investigators used gestation-only colonization and germ-free delivery to ensure that any change in neonatal immune composition was limited to encounters with the maternal microbiota only during gestation. At 14 days post-birth it was shown that elevated numbers of early post-natal intestinal innate leukocytes, specifically the NKp46+ROR?t+ ILC3 subpopulaiton, as well as intestinal F4/80+CD11c+ mononulcear cells (iMNC) were present in pups born to gestation-only colonized dams compared to germ-free controls. Counter to the innate leukocyte alterations seen in the germ-free animals, the adaptive immune composition of the neonates was not impacted. No difference was seen in T or B cell levels in the central or peripheral lyphoid organs as well as systemic CD4 or CD8 T cell numbers. Investigators went on to show significant changes to the transcriptional programming in the intestinal epithelium. These transcriptional changes included upregulation of gene networks repsonsible for a wide range of intestinal functions that were previoulsy associated with post-natal colonization, indicating that maternal microbial colonization may shape not only the early post-natal immune response but intestinal epithelial development as well. Alterations to the NKp46+ ILC3 populations relied upon maternal antibodies, with the effect being successfully recapitulated through serum transfer from colonized to non-colonized dams. This effect was lost however when the serum was depleted of IgG, indicating an antibody driven mechanism. Interestingly, when antibody-deficient pregnant dams were transiently colonized the increase in NKp46+ ILC3, but not the F4/80+CD11c+ iMNC subpopulations was lost. This indicated that a different mechanism for the increase in iMNC was present. An extensive range of bacteria-derived molecules were shown to be transferred from the mother to the offspring as well. In short, it was determined that contrary to general concensus the early post-natal immune system, as well as intestinal development is shaped by interaction with the maternal microbiota.
We will now examine this intertaction between maternal microbiota and the prenate, in the presence of inflammation, and its promotion of neurodevelopmental abnormalities (3) and autism like phenotypes (4). Both Choi et al. 2016, and Kim et al. 2017, describe the degenerative effects of IL-17a on neurodevelopment and the resulting ASD-like phenotypes in the offspring of mothers who underwent a Th17 inducing inflammatory response. In Choi, et al. 2016, it was shown that elevated levels of maternal IL-17a induced from MIA resulted in abnormal cortical development in offspring. Injection of a viral mimic, poly(I:C), during gestation resulted in elevated levels of IL-6, TNF?, IFN-?, and IL-1? almost immediately, followed by a strong increase inserum levels of IL-17a approximately 2 days later. It was previously shown that IL-6 is necessary for Th17 cell differentiation (10) and plays a key intermediary role in multiple neurological disorders (6). This was reinforced when IL-6 KOt mice failed to to increase serum levels of IL-17a when injected with poly(I:C) and conversely when wild-type mothers injected with IL-6 showed greater IL-17a responses, validating IL-6 as a necessary upstream precursor to IL-17a. Increases in maternal circulating IL-17a resulted in augmentation of IL-17a receptor (IL-17Ra) in the fetal brain.
Upregulation of maternal IL-17a resulted in abnormal cortical development which promoted ASD-like phenotypes such as repetitive and anti-social behaviors (4). Injections of IL-17a directly into the fetal brain in the absence of MIA resulted in similar but not identical abnormal cortical development suggesting that some pre-existing inflammation is necessary to fully reproduce the cortical disorganization seen in ASD-like offspring. ROR?t expression in maternal T cells was also shown to be necessary for the development of ASD-like phenotypes in MIA offspring, further supporting the hypothesis that a Th17 inducing inflammatory response is required to promote the ASD-like phenotype in mice. Finally, it was demonstrated that in the presence of inflammation either knock out of ROR?t espression or IL-17a-blocking antibody given to pregnant dams were able to rescue the ASD-like phenotype from MIA offspring. Indicating both may be effective therapeutic targets. Kim et al. 2017, was able to further elucidate this complicated interplay between inflammation, MIA, and pregnancy. Pregnant dams injected with poly(I:C) followed by treatment with vancomycin decreased the the proportion of Th17 cells in the intestine and reduced the levels of IL-17a in the maternal plasma. Segmented fillamentous bacteria (SFB) were identified as being both susceptibel to vancomycin (11) and greatly contribute to intestinal Th17 cell propogation (12). Naturaly occuring differences in SFB in different mice strains were used to validate this hypothesis. Showing SFB colonization resulted in an increase in pre-existing Th17 cells as indicated by a very rapid increase in plasma IL-17a levels.
The complex link between the maternal microbiota, the maternal immune system, and their combined effects on the developing fetus is just beginning to be understood. Numerous avenues from which to pursue these relationships are apparent, and these datas point towards a few key points that have yet to be elucidated. The first being ROR?t and its dichotomous role. For instance, when expressed in NKp46+ ILC3 or iLT cells its role appears somewhat protective (13), compared to its role in T cells inducing pro-inflammatory Th17 cell differentiation resulting in increased levels of IL-17a and the described effects on neurological development. Secondly the unique intestinal milieu of pregnancy and why it appears a necessary requirement for the secretion of key intermediary cytokines IL-1?, IL-6, and IL-23 upstream of IL-17a (3). Changes in the maternal microbiome have previously been shown to increase levels of Bacteroides and Staphylococcus species especially mothers with comorbidities (14). As aberrant ratios of Bacteriodes species were identified as a potential role player in MIA pathogenesis (2) it would be interesting perhaps to investigate if there is a hormonal effect at play here.
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